This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The gastrointestinal tract (GIT) is a major target of infection with HIV/SIV. Chronic GIT disease and inflammation are common sequelae to HIV/SIV infection. Nonetheless, the molecular mechanisms that cause and maintain GIT dysfunction remain unclear. We investigated the contribution of C/EBP-beta to GIT disease and viral replication, in jejunum and colon collected at necropsy from 12 SIV-infected (group 1) or 10 uninfected macaques with chronic diarrhea (group 2) and 9 uninfected control macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting and colitis but group 1 animals had more severe lesions in the jejunum. C/EBP-beta gene expression was significantly increased in colon of group 1 and 2 and in jejunum of only group 1 macaques compared to controls. In group 1 animals, CEBP-beta expression was localized predominantly to macrophages and rarely lymphocytes. Chromatin Immunoprecipiatation (ChIP) assays confirmed the binding of C/EBP-beta and p65 to the SIV LTR in colonic lamina propria cells suggesting a mechanistic link between inflammation and activation of viral replication in vivo. This is the first in vivo study describing the transcriptional changes and immunophenotypic localization of C/EBP-beta in the GIT of SIV-infected macaques. More importantly, the data provides a molecular mechanism for persistent inflammation and immune activation leading to increased SIV burden and GIT pathology in SIV-infected macaques and perhaps HIV-infected individuals.